Successful Live Twin Birth through IVF/ICSI from a Couple with an Infertile Father with Pericentric Inversion of Chromosome 9 (p12q13): A Case with a High Aneuploidy Rate.

Evidence suggests that the pericentric inversion of chromosome 9 (inv(9)) does not affect the aneuploidy rate (38.5%) after IVF. Herein, we report a successful live female twin birth through IVF/ICSI with a high aneuploidy rate from a couple within which the infertile father has inv(9)(p12q13). A couple (a 34-year-old male and a 35-year-old female) was referred to our clinic due to infertility. The wife has a child with her previous husband. Results from the infertility workup of both parents were normal. Karyotyping revealed that the inv(9)(p12q13) of the father was the only cytogenetic abnormality. Preimplantation genetic testing for aneuploidies (PGT-A) after IVF/ICSI revealed a high aneuploidy rate (77%; 10/13). Two euploid blastocysts were transferred, resulting in a successful live female twin birth. The presented case highlights the possibility that inv(9)(p12q13) in males may impact the fertility and euploidy rate. PGT-A facilitates the selection of qualified blastocysts for the optimization of live-birth outcomes.

Recombinant Chromosome 7 Driven by Maternal Chromosome 7 Pericentric Inversion in a Girl with Features of Silver-Russell Syndrome.

Maternal uniparental disomy of chromosome 7 is present in 5-10% of patients with Silver-Russell syndrome (SRS), and duplication of 7p including GRB10 (Growth Factor Receptor-Bound Protein 10), an imprinted gene that affects pre-and postnatal growth retardation, has been associated with the SRS phenotype. Here, we report on a 17 year old girl referred to array-CGH analysis for short stature, psychomotor delay, and relative macrocephaly. Array-CGH analysis showed two copy number variants (CNVs): a ~12.7 Mb gain in 7p13-p11.2, involving GRB10 and an ~9 Mb loss in 7q11.21-q11.23. FISH experiments performed on the proband's mother showed a chromosome 7 pericentric inversion that might have mediated the complex rearrangement harbored by the daughter. Indeed, we found that segmental duplications, of which chromosome 7 is highly enriched, mapped at the breakpoints of both the mother's inversion and the daughter's CNVs. We postulate that pairing of highly homologous sequences might have perturbed the correct meiotic chromosome segregation, leading to unbalanced outcomes and acting as the putative meiotic mechanism that was causative of the proband's rearrangement. Comparison of the girl's phenotype to those of patients with similar CNVs supports the presence of 7p in a locus associated with features of SRS syndrome.

Pericentric inversion (Inv) 9 variant-reproductive risk factor or benign finding?

PURPOSE: To report the unbalanced chromosome rearrangement rate and overall aneuploidy rate in day 5/6 embryos from a series of patients who underwent in vitro fertilization (IVF) with preimplantation genetic testing for structural rearrangements (PGT-SR) for the pericentric inversion 9 variant, inv(9)(p11q13) or inv(9)(p12q13), with concurrent 24 chromosome preimplantation genetic testing for aneuploidy (PGT-A). METHODS: This was a retrospective cohort analysis. IVF cycles and embryo biopsies were performed by referring clinics. Fifty-two trophectoderm biopsy samples from seven couples were sent to a single lab for PGT-SR for an inversion 9 variant with concurrent 24 chromosome PGT-A using single-nucleotide polymorphism (SNP) microarrays with bioinformatics. RESULTS: The unbalanced rearrangement rate for this embryo cohort was 0/52 (0.0%); mean maternal age per embryo was 33.3 years (range 21-39 years). The overall euploid rate was 61.5% and aneuploidy rate was 38.5%. CONCLUSIONS: Chromosome 9 pericentric inversions did not result in unbalanced structural rearrangements in day 5/6 embryo samples, supporting that this population variant is not associated with increased reproductive risks.

A Girl with 10 Mb Distal Xp Deletion Arising from Maternal Pericentric Inversion: Clinical Data and Molecular Characterization.

BACKGROUND: Short arm deletions of the X-chromosome are challenging issues for genetic counseling due to their low penetrance in population. Female carriers of these deletions have milder phenotype than male ones, considering the intellectual ability and social skills, probably because of the X-chromosome inactivation phenomenon. CASE REPORT: A female patient with a 10Mb distal Xp deletion and an Xq duplication, showing mild intellectual disability, is described in this report. While the deletion arose from a maternal pericentric inversion, the duplication was directly transmitted from the mother who is phenotypically normal. CONCLUSION: This report underlines the usefulness of molecular cytogenetic technics in postnatal diagnosis.

A boy with partial dup(18q)/del(18p) due to a maternal pericentric inversion: Genotype-phenotype correlation and risk of recombinant chromosomes based on systematic review of the literature.

We report a boy carrying a recombinant chromosome 18, with terminal deletion of 10.8 Mb from 18p11.32 to 18p11.21 and a terminal duplication of 22.8 Mb from 18q21.31 to 18q23, resulting from a maternal pericentric inversion of the chromosome 18. He presented with poor growth, developmental delay, facial dysmorphisms, surgically repaired left cleft lip and palate, a mild form of holoprosencephaly characterized by single central incisor and agenesis of the septum pellucidum, and body asymmetry. Based on the systematic review of the literature, we discuss genotype-phenotype correlation and the risk for the recombinants of pericentric inversions of chromosome 18. © 2016 Wiley Periodicals, Inc.

Recurrent proximal 18p monosomy and 18q trisomy in a family due to a pericentric inversion.

Here, we report on a family with pericentric inversion of chromosome 18 [inv(18)(p11.2q21)] and two recombinants with a duplication of q21 → qter and a deletion of p11.2 → pter regions in a four-generation family. This chromosomal abnormality was inherited in our first patient from the father, while it was transmitted to the second patient from the mother. Array-CGH analysis were used to better characterize duplicated and deleted chromosomal regions and showed no genomic copy number variation (CNV) differences between these two relatives. We discussed genotype-phenotype correlations including previously reported.

Duplication of 20qter and deletion of 20pter due to paternal pericentric inversion: patient report and review of 20qter duplications.

Duplications of the terminal long arm of chromosome 20 are rare chromosomal anomalies. We report a male infant found on array comparative genomic hybridization analysis to have a 19.5 Mb duplication of chromosome 20q13.12-13.33, as well as an 886 kb deletion of 20p13 at 18,580-904,299 bp. This anomaly occurred as the recombinant product of a paternal pericentric inversion. There have been 23 reported clinical cases involving 20qter duplications; however, to our knowledge this is only the second reported patient with a paternal pericentric inversion resulting in 46,XY,rec(20)dup(20q). This patient shares many characteristics with previously described patients with 20qter duplications, including microphthalmia, anteverted nares, long ears, cleft palate, small chin, dimpled chin, cardiac malformations, and normal intrauterine growth. While there is variable morbidity in patients with terminal duplications of 20q, a review of previously reported patients and comparison to our patient's findings shows significant phenotypic similarity.

Pre- and postnatal findings in a patient with a novel rec(8)dup(8q)inv(8)(p23.2q22.3) associated with San Luis Valley syndrome.

San Luis Valley syndrome, which is due to a recombinant chromosome 8 (SLV Rec8) found in Hispanic individuals from Southwestern United States, is a well-established syndrome associated with intellectual disabilities and, frequently, severe cardiac anomalies. We report for the first time on a Moroccan girl with a recombinant chromosome 8 prenatally diagnosed as SLV Rec8 by conventional cytogenetic studies. At birth, an oligo array-CGH (105 K) defined the breakpoints and the size of the imbalanced segments, with a deletion of ≈ 2.27 Mb (8p23.2-pter) and a duplication of ≈ 41.93 Mb (8q22.3-qter); thus this recombinant chromosome 8 differed from that previously reported in SLV Rec8 syndrome. The phenotypic characteristics associated with this SLV Rec8 genotype overlap those commonly found in patients with 8q duplication reported in the literature. We review SLV Rec8 and other chromosome 8 aberrations and suggest that the overexpression of cardiogenic genes located at 8q may be the cause of the cardiac defects in this patient.

3q26.2/MECOM Rearrangements by Pericentric Inv(3): Diagnostic Challenges and Clinicopathologic Features.

MECOM rearrangement (MECOM-R) resulting from 3q26.2 aberrations is often associated with myeloid neoplasms and inferior prognosis in affected patients. Uncommonly, certain 3q26.2/MECOM-R can be subtle/cryptic and consequently overlooked by karyotyping. We identified 17 acute myeloid leukemia (AML) patients (male/female: 13/4 with a median age of 67 years, range 42 to 85 years) with a pericentric inv(3) leading to MECOM-R, with breakpoints at 3p23 (n = 11), 3p25 (n = 3), 3p21 (n = 2) and 3p13 (n = 1) on 3p and 3q26.2 on 3q. These pericentric inv(3)s were overlooked by karyotyping initially in 16 of 17 cases and later detected by metaphase FISH analysis. Similar to the patients with classic/paracentric inv(3)(q21q26.2), patients with pericentric inv(3) exhibited frequent cytopenia, morphological dysplasia (especially megakaryocytes), -7/del(7q), frequent NRAS (n = 6), RUNX1 (n = 5) and FLT-3 (n = 4) mutations and dismal outcomes (median overall survival: 14 months). However, patients with pericentric inv(3) more frequently had AML with thrombocytopenia (n = 15, 88%), relative monocytosis in peripheral blood (n = 15, 88%), decreased megakaryocytes (n = 11, 65%), and lower SF3B1 mutation. We conclude that AML with pericentric inv(3) shares some similarities with AML associated with classic/paracentric inv(3)/GATA2::MECOM but also shows certain unique features. Pericentric inv(3)s are often subtle/cryptic by chromosomal analysis. A reflex FISH analysis for MECOM-R is recommended in myeloid neoplasms showing -7/del(7q).

Pericentric Inversion of Chromosome 9 in Twins With Cyclopia: A Rare Entity.

Pericentric inversion of chromosome 9 (inv(9)) is one of the most common variants seen in a normal human karyotype that occurs during meiosis. Despite being categorized as a normal variant, some studies using classical cytogenetics have recently shown that inv(9) could be associated with azoospermia, congenital anomalies, growth retardation, and rarely with abnormal karyotype. However, there is no reported association with cyclopia. Interestingly this genetic variant involves twin fetuses. A 36-year-old multiparous lady with dichorionic diamniotic twin pregnancy presented to the fetomaternal unit with fetal growth restriction at 34 weeks of gestation. An ultrasound scan revealed both have microcephaly, fisting hands, holoprosencephaly, and proboscis suspicious of Patau syndrome. Amniocentesis was not issued due to late pregnancy and guarded prognosis. The mother presented with pre-eclampsia at 35 weeks of gestation. The pregnancy managed to prolong up to 36 weeks after which caesarean section was performed due to the leading twin being in a transverse lie. Two baby twin girls were born 3 minutes apart with microcephaly and cyclops appearance. Chromosomal analysis of both twins revealed similar karyotypes of 46, XX, inv(9)(p11,q13). Pericentric inversion of chromosome 9 is regarded as a normal chromosomal variation in the general population, but in twins with cyclops is considered rare. Early referral to a tertiary hospital for twin management is highly required. It may identify fetuses with such abnormalities and counsel the parents with appropriate management.

Prenatal diagnosis and molecular cytogenetic characterization of partial dup (18p)/del (18q) due to a maternal pericentric inversion 18 in a foetus with multiple anomalies.

OBJECTIVE: The 18q terminal deletion with inverted duplication is an extremely rare abnormality, with only three confirmed cases in Europe to date. Here, we report, for the first time, a case of de novo 18q inv-dup-del in a Turkish pregnant woman. CASE REPORT: A 30-year-old pregnant woman was referred for genetic analysis at her 25th gestational week due to foetal diaphragmatic hernia and rocker bottom feet. Cytogenetic analysis of the parents revealed a karyotype of 46,XX,inv(18) (p11.3q21.3) of the mother and a normal karyotype of the father. The foetal karyotype was defined as 46,XX,rec(18)del(18q)inv(18) (p11.3q21.3)mat. CONCLUSION: To our knowledge, this is the first report of a prenatal diagnosis. Genetic counselling issues for this family, particularly affected individuals, include an increased likelihood of reduced fertility and a risk of recurrence of parental inversion equal to 1/2 in surviving offspring.

Pericentric inversion of chromosome 6 and male fertility problems.

As a significant chromosomal structural abnormality, chromosomal inversion is closely related to male infertility. For inversion carriers, the interchromosomal effect explains male infertility, but its specific mechanism remains unclear. Additionally, inversion carriers with different chromosomes have different clinical manifestations. Therefore, genetic counseling is difficult in clinical practice. Herein, four male carriers of pericentric inversion in chromosome 6 have been described. Two patients showed asthenospermia, one showed azoospermia, and the wife of the remaining patient had recurrent miscarriages. Through a literature search, the association between the breakpoint of pericentric inversion in chromosome 6 and male fertility problems are also discussed in this study. Overall, important genes related to asthenospermia in chromosome 6p21 were found, which may be related to the clinical phenotype. These results suggest that physicians should focus on the breakpoints of inversion in genetic counseling.

Chromosome 9 Inversion: Pathogenic or Benign? A Comprehensive Systematic Review of all Clinical Reports.

BACKGROUND: Inversion of chromosome 9 (inv[9]) is known as one of the most common structural balanced chromosomal variations. Chromosome 9 is highly susceptible to structural rearrangements, specifically to pericentric inversions. Various investigators have posited that inv(9) with different breakpoints could be the cause of several abnormal conditions in individuals, whereas others have considered it a benign variant. To our knowledge, a consensus regarding the effects of this inversion has yet to emerge. OBJECTIVE: This study aims to discuss the pathogenic/benign effects of inv(9) in all possible clinical conditions detected in the occurrence of this abnormality. METHODS: Studies on inv(9) were collected via PubMed, MalaCards, Google Scholar, and NORD, along with the search terms of inv(9), pericentric inv(9), and chromosome 9 variants. Additionally, the incidence of inv(9) and the karyotype and clinical findings of individuals reported with this variant were investigated. RESULTS: The collection of the studies reviewed shows that inv(9) is associated with various conditions such as congenital anomalies, growth retardation, infertility, recurrent pregnancy loss, and cancer. The clinical features associated with this variant in humans vary between growth stages. Further, there have been no shared clinical findings in a specific period. CONCLUSION: Although there is no conclusive evidence for the pathogenicity of this rearrangement, prenatal genetic counseling on inv(9) and further clinical and molecular studies would be helpful in chromosome 9-related problems.

Molecular cytogenetic analysis of partial monosomy 10p and trisomy 10q resulting from familial pericentric inversion (10): a first case report in Chinese population.

BACKGROUND: Chromosome aberrations of 10p monosomy and 10q trisomy resulting from parental pericentric inversion 10 are extremely rare, and to date, very few reports have been published on the matter. CASE PRESENTATION: A 30-year-old pregnant woman with recurrent pregnancy loss is enrolled in this research. In this pregnancy, spontaneous abortion occurred in the first trimester of her pregnancy. Chromosomal microarray analysis of the abortion tissue showed a partial 10p monosomy (arr[GRCh37] 10p15.3p11.21(100,047_34,848,853) × 1) and a duplication of 10q (arr[GRCh37] 10q26.13q26.3(126,093,990_135,426,386) × 3). Further parental karyotype analysis indicated that the chromosomal abnormalities in the fetus was resulted from paternal pericenric inversion inv(10)(p11.21q26.13). This study presents the first case of a large deletion of 10p combined with 10q trisomy, resulting in pregnancy loss. Of these two manifestations, the large deletion of chromosome 10p may be the primary reason for spontaneous abortion in this subject. CONCLUSIONS: This study presents the first case of partial 10p monosomy associated with 10q trisomy in Chinese population. It provides more information on the chromosome aberration of 10p monosomy and 10q trisomy and further strengthens the application value of microarray in the molecular etiological diagnosis of recurrent spontaneous abortion.

Cytogenetic Screening in Couples with Recurrent Pregnancy Loss: A Single-Center Study and Review of Literature.

CONTEXT: Recurrent pregnancy loss (RPL) is a devastating reproductive problem that affects more than 2% of couples who are trying to conceive. Chromosomal rearrangements in either carrier are a major cause of clinically recognized abortion. AIMS: The purpose of this study is to report the prevalence of chromosome abnormalities in RPL and provide clinical characteristics of couples with two and more miscarriages. SETTINGS AND DESIGN: Genetic counseling in laboratory of histology housed in a Faculty of Medicine of Sfax. MATERIALS AND METHODS: Karyotype was generated from the peripheral blood lymphocyte cultures and the cytogenetic analysis was performed using R-bands after heat denaturation and Giemsa (RHG) banding. A multiplex polymerase chain reaction wherever necessary was done. STATISTICAL ANALYSIS USED: SPSS version 17. RESULTS: A total of 104 couples with RPL were carried out in this study. The frequency of chromosomal rearrangements was 11.5%, three times more prevalent in men than women (P = 0.08). In addition, the prevalence of chromosomal anomalies increases according to the number of miscarriages (from 4.8% to 7.6%, with 2 or ≥3 miscarriages, respectively; P = 0.9). Finally, a particular familial adverse reproductive background was found in these carriers (P = 0.03). CONCLUSIONS: These data highlight that an RPL evaluation is appropriate after the second miscarriage and that cytogenetic evaluation is necessary for an accurate approach to elucidate the causes of RPL. Moreover, familial adverse reproductive backgrounds have an impact of being carrier of chromosome abnormalities and a larger study is mandatory to define reproductive characteristics of carriers.

Characterization of a pericentric inversion in plateau fence lizards (Sceloporus tristichus): evidence from chromosome-scale genomes.

Spiny lizards in the genus Sceloporus are a model system among squamate reptiles for studies of chromosomal evolution. While most pleurodont iguanians retain an ancestral karyotype formula of 2n = 36 chromosomes, Sceloporus exhibits substantial karyotype variation ranging from 2n = 22 to 46 chromosomes. We present two annotated chromosome-scale genome assemblies for the Plateau Fence Lizard (Sceloporus tristichus) to facilitate research on the role of pericentric inversion polymorphisms on adaptation and speciation. Based on previous karyotype work using conventional staining, the S. tristichus genome is characterized as 2n = 22 with six pairs of macrochromosomes and five pairs of microchromosomes and a pericentric inversion polymorphism on chromosome 7 that is geographically variable. We provide annotated, chromosome-scale genomes for two lizards located at opposite ends of a dynamic hybrid zone that are each fixed for different inversion polymorphisms. The assembled genomes are 1.84-1.87 Gb (1.72 Gb for scaffolds mapping to chromosomes) with a scaffold N50 of 267.5 Mb. Functional annotation of the genomes resulted in ∼15K predicted gene models. Our assemblies confirmed the presence of a 4.62-Mb pericentric inversion on chromosome 7, which contains 62 annotated coding genes with known functions. In addition, we collected population genomics data using double digest RAD-sequencing for 44 S. tristichus to estimate population structure and phylogeny across the Colorado Plateau. These new genomic resources provide opportunities to perform genomic scans and investigate the formation and spread of pericentric inversions in a naturally occurring hybrid zone.

Pericentric inversion in chromosome 1 and male infertility.

Pericentric inversion in chromosome 1 was thought to cause male infertility through spermatogenic impairment, regardless of the breakpoint position. However, carriers of pericentric inversion in chromosome 1 have been reported with normal fertility and familial transmission. Here, we report two cases of pericentric inversion in chromosome 1. One case was detected in utero via amniocentesis, and the other case was detected after the wife of the carrier experienced two spontaneous abortions within 5 years of marriage. Here, the effect of the breakpoint position of the inversion in chromosome 1 on male infertility is examined and compared with the published cases. The association between the breakpoint of pericentric inversion in chromosome 1 and spermatogenesis is also discussed. Overall, the results suggest that the breakpoint position deserves attention from physicians in genetic counseling as inversion carriers can produce offspring.

22q13 Microduplication Syndrome in Siblings with Mild Clinical Phenotype: Broadening the Clinical and Behavioral Spectrum.

Distal duplication 22q (22q13.3qter) is a rare condition with only 24 cases described so far. Parental balanced reciprocal translocations and pericentric inversions involving chromosome 22 predispose to the conception of an unbalanced offspring and are more frequently reported than de novo events. The clinical phenotype of patients is highly variable and does not necessarily correlate with the extent of the duplicated segment. Short stature, microcephaly, hypertelorism, cleft lip or palate, low-set ears, and intellectual disability seem to be the most consistent features. Familial reoccurrence is extremely rarely reported. Here, we report 2 siblings with a 22q13.3qter duplication detected by array CGH; their mother is a carrier of a pericentric inversion in chromosome 22. Their relatively mild phenotype and identical chromosomal breakpoints as well as duplication size are unique. This is the first case described so far.

Karyotype Evolution in 10 Pinniped Species: Variability of Heterochromatin versus High Conservatism of Euchromatin as Revealed by Comparative Molecular Cytogenetics.

Pinnipedia karyotype evolution was studied here using human, domestic dog, and stone marten whole-chromosome painting probes to obtain comparative chromosome maps among species of Odobenidae (Odobenus rosmarus), Phocidae (Phoca vitulina, Phoca largha, Phoca hispida, Pusa sibirica, Erignathus barbatus), and Otariidae (Eumetopias jubatus, Callorhinus ursinus, Phocarctos hookeri, and Arctocephalus forsteri). Structural and functional chromosomal features were assessed with telomere repeat and ribosomal-DNA probes and by CBG (C-bands revealed by barium hydroxide treatment followed by Giemsa staining) and CDAG (Chromomycin A3-DAPI after G-banding) methods. We demonstrated diversity of heterochromatin among pinniped karyotypes in terms of localization, size, and nucleotide composition. For the first time, an intrachromosomal rearrangement common for Otariidae and Odobenidae was revealed. We postulate that the order of evolutionarily conserved segments in the analyzed pinnipeds is the same as the order proposed for the ancestral Carnivora karyotype (2n = 38). The evolution of conserved genomes of pinnipeds has been accompanied by few fusion events (less than one rearrangement per 10 million years) and by novel intrachromosomal changes including the emergence of new centromeres and pericentric inversion/centromere repositioning. The observed interspecific diversity of pinniped karyotypes driven by constitutive heterochromatin variation likely has played an important role in karyotype evolution of pinnipeds, thereby contributing to the differences of pinnipeds' chromosome sets.

Effects of chromosome 9 inversion on IVF/ICSI: A 7-year retrospective cohort study.

BACKGROUND: This study focused on the outcomes of patients with pericentric inversion of chromosome 9 who underwent IVF/ICSI and fresh day 2 or day 3 embryo transfer and the possible impacts of carrier gender and chromosome karyotype on pregnancy outcomes. METHODS: A total of 214 couples (107 couples with one pericentric inversion of chromosome 9 in one partner [Group 1], 107 couples with normal karyotypes [Group 2]) underwent their first IVF/ICSI treatment and were included in this study. Oocyte number, normal fertilization rates, abnormal fertilization rates, cleavage rates, embryo utilization rates, fresh embryo transfer rates, clinical pregnancy rates (CPR), implantation rates, miscarriage rates, and live birth rates per embryo transfer (LBR) were compared between groups. RESULTS: Group 1 did not show any disadvantage when compared with Group 2. The CPR and LBR were similar between all groups. The female carrier group had a higher normal fertilization rate and higher utilization rate than the male carrier group. Cases with inv(9)(p12;q13) had a lower utilization rate but a higher implantation rate than the remaining karyotypes. CONCLUSION: In the first IVF or ICSI cycle, couples with one pericentric inversion of chromosome 9 in one partner had satisfactory outcomes. The subgroup analysis showed a tendency of better prognosis for the female carrier and inv(9)(p12;q13) type.